Hemophagocytic lymphohistiocytosis (HLH) is a disorder of abnormal and severely damaging immune activation. Despite recent medical progress, significant numbers of children with HLH still die during the initial phases of therapy. Notably, two different approaches for treating HLH, with similar outcomes, have been reported. We are proposing to conduct a clinical trial, called the 'Hybrid Immunotherapy for HLH' (HIT-HLH) trial, which tests the idea that a treatment regimen combining aspects of both approaches (ATG and etoposide) may result in better outcomes for patients with HLH. By conducting this multicenter pilot trial, the HIT-HLH consortium hopes to define response and survival rates with significant precision after treatment with this innovative regimen. We also hope to correlate outcomes of these patients with extensive clinical data collected on study participants. These goals are important because advancing therapy for this devastating disorder will require large trials comparing standard treatment with this (or other) new innovative therapies. These trials cannot be performed without first testing the new 'hybrid' approach and understanding how feasible and effective it may be. These studies are also important because there are no known clinical features which can predict relapse or death in patients with HLH, and such knowledge will be essential for tailoring future therapies to patients needs. Furthermore, conducting the HIT-HLH trial will gather together a uniquely qualified network of collaborative investigators who are interested and motivated to test novel therapies for patients with HLH. The impact and efforts of this network will extend well beyond the current trial. Through this effort we intend to improve the long term survival of children with HLH and develop significant new insights into HLH and human immune function. PUBLIC HEALTH RELEVANCE: Hemophagocytic lymphohistiocytosis (HLH) is a disorder of abnormal and severely damaging immune activation. We are proposing to conduct a clinical trial, called the' Hybrid Immunotherapy for HLH' (HIT-HLH) trial, which tests a treatment regimen combining aspects of currently divergent therapeutic strategies (ATG and etoposide). Through this trial and subsequent studies, we intend to improve the long-term survival of children with HLH and develop significant new insights into HLH and human immune function. (End of Abstract)